Synthesis and Pharmacological Evaluation of Enantiopure N-Substituted Ortho-c Oxide-Bridged 5-Phenylmorphans

Fuying Li, Theresa A. Kopajtic, Jonathan L. Katz, Dan Luo, Thomas E. Prisinzano, Gregory H. Imler, Jeffrey R. Deschamps, Arthur E. Jacobson, Kenner C. Rice

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1 Scopus citations

Abstract

The design of enantiopure stereoisomers of N-2-phenylcyclopropylmethyl-substituted ortho-c oxide-bridged phenylmorphans, the E and Z isomers of an N-cinnamyl moiety, and N-propyl enantiomers were based on combining the most potent oxide-bridged phenylmorphan (the ortho-c isomer) with the most potent N-substituent that we previously found with a 5-(3-hydroxy)phenylmorphan (i.e., N-2-phenylcyclopropyl methyl moieties, N-cinnamyl, and N-propyl substituents). The synthesis of the eight enantiopure N-2-phenylcyclopropylmethyl ortho-c oxide-bridged phenylmorphans and six additional enantiomers of the N-substituted ortho-c oxide-bridged phenylmorphans (N-E and Z-cinnamyl compounds, and N-propyl compounds) was accomplished. The synthesis started from common intermediates (3R,6aS,11aS)-10-methoxy-1,3,4,5,6,11a-hexahydro-2H-3,6a-methano-benzofuro[2,3-c]azocine (+)-6 and its enantiomer, (3S, 6aR, 11aR)-(-)-6, respectively. The enantiomers of ±-6 were obtained through salt formation with (S)-(+)- and (R)-(-)-p-methylmandelic acid, and the absolute configuration of the (R)-(-)-p-methylmandelate salt of (3S, 6aR, 11aR)-(-)-6 was determined by single-crystal X-ray analysis. The enantiomeric secondary amines were reacted with N-(2-phenylcyclopropyl)methyl derivatives, 2-(E)-cinnamyl bromide, and (Z)-3-phenylacrylic acid. These products led to all of the desired N-derivatives of the ortho-c oxide-bridged phenylmorphans. Their opioid receptor binding affinity was measured. The compounds with MOR affinity < 50 nM were examined for their functional activity in the forskolin-induced cAMP accumulation assay. Only the enantiomer of the N-phenethyl ortho-c oxide-bridged phenylmorphan ((-)-1), and only the (3S,6aR,11aR)-2-(((1S,2S)-2-phenylcyclopropyl)methyl)-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol isomer ((+)-17), and the N-phenylpropyl derivative ((-)-25) had opioid binding affinity < 50 nM. Both (-)-1 and (-)-25 were partial agonists in the cAMP assay, with the former showing high potency and low efficacy, and the latter with lower potency and less efficacy. Most interesting was the N-2-phenylcyclopropylmethyl (3S,6aR,11aR)-2-(1S,2S)-enantiomer ((+)-17). That compound had good MOR binding affinity (Ki = 11.9 nM) and was found to have naltrexone-like potency as a MOR antagonist (IC50 = 6.92 nM).

Original languageEnglish
Article number8808
JournalMolecules
Volume27
Issue number24
DOIs
StatePublished - Dec 2022

Bibliographical note

Publisher Copyright:
© 2022 by the authors.

Funding

The work of F.L., A.E.J. and K.C.R. was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism. The work of T.A.K. and J.L.K. was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse. This work was supported in part by NIDA grant DA051377 (to T.E.P.) and the Kentucky Medical Services Foundation Endowed Chair in Pharmacy (T.E.P.). The X-ray crystallographic work was supported by NIDA, NIH, and DHHS, through an Interagency Agreement #Y1-DA1101 with the Naval Research Laboratory (NRL). G.H.I. thanks the Office of Naval Research (Award No. N00014-15-WX-0-0149).

FundersFunder number
Kentucky Medical Services Foundation
National Institutes of Health (NIH)
Office of Naval ResearchN00014-15-WX-0-0149
U.S. Department of Health and Human Services1-DA1101
National Institute on Drug AbuseN01DA001101, DA051377
National Institute on Alcohol Abuse and Alcoholism
U.S. Naval Research Laboratory

    Keywords

    • DAMGO
    • DOR
    • KOR
    • MOR
    • [D-Ala2; N-Me-Phe4; Gly5-ol]-enkephalin
    • cAMP
    • cyclic adenosine monophosphate
    • fluorescent Ca2+ mobilization assays
    • ortho-c oxide-bridged 5-phenylmorphans
    • δ-opioid receptor
    • κ-opioid receptor
    • μ-opioid receptor

    ASJC Scopus subject areas

    • Analytical Chemistry
    • Chemistry (miscellaneous)
    • Molecular Medicine
    • Pharmaceutical Science
    • Drug Discovery
    • Physical and Theoretical Chemistry
    • Organic Chemistry

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